This application is a national stage filing of PCT International Application No. PCT/F199/00793, filed on Sep. 27, 1999, which published in the English language.
The present invention relates to a new method of administering 3-(1H-imidazol-4-ylmethyl)-indan-5-ol, its enantiomer or a pharmaceutically acceptable ester or salt thereof. Accordingly, the present invention relates to an intraspinal administration of 3-(1H-imidazol-4-ylmethyl)-indan-5-ol, its enantiomer or a pharmaceutically acceptable ester or salt thereof to obtain analgesia. The intraspinal administration is intented to include epidural, intrathecal and intrarrhachidian administration. Accordingly, the present invention relates to a method for obtaining analgesia in a mammal by administering 3-(1H-imidazol-4-ylmethyl)-indan-5-ol, its enantiomer or a pharmaceutically acceptable ester or salt thereof intraspinally. Particularly, the present invention relates to an intraspinal administration of 3-(1H-imidazol-4-ylmethyl)-indan-5-ol, its enantiomer or a pharmaceutically acceptable ester or salt thereof for obtaining analgesia without sedation. Further, the present invention relates to a method of using 3-(1H-imidazol-4-ylmethyl)-indan-5-ol, its enantiomer or a pharmaceutically acceptable ester or salt thereof as an adjunct to anaesthesia by administering the drug intraspinally. The present invention also relates to a method for treating a mammal by administering 3-(1H-imidazol-4-ylmethyl)-indan-5-ol, its enantiomer or a pharmaceutically acceptable ester or salt thereof intraspinally. Further, the present invention relates to the use of 3-(1H-imidazol-4-ylmethyl)-indan-5-ol, its enantiomer or a pharmaceutically acceptable ester or salt in the manufacture of a medicament for intraspinal administration.
3-(1H-Imidazol-4-ylmethyl)-indan-5-ol has the following formula: 
3-(1H-Imidazol-4-ylmethyl)-indan-5-ol is described in WO 97/12874 as an xcex12-receptor agonist useful in the treatment of hypertension, glaucoma, migraine, diarrhea, ischemia, addiction to chemical substances, anxiety, especially preoperative anxiety, and different neurological, musculosketal, psychiatric and cognition disorders as well as a sedative and an analgesic agent, nasal decongestant, and as an adjunct to anaesthesia. Enteral, topical, and parenteral routes of administration and a method for producing the compound are discussed in WO 97/12874.
Opioids, especially morphine, are routinely used for intraspinal and epidural administration to give analgesia. However, according to Eisenach J. E. (Exp. Opin. Invest. Drugs 3(10), 1994, 1005-1010) the major concern limiting the use of intraspinal morphine is the 0.1 to 0.2% incidence of severe respiratory depression, occurring six to twelve hours after injection.
xcex12-Receptor agonists are being evaluated for obtaining analgesia by administering them intrathecally or epidurally. At the moment, the only xcex12-receptor agonist approved by the FDA for obtaining analgesia by epidural administration is clonidine (DURACLONO(copyright)). According to Laitin S. and Wallac M. (xe2x80x9cxcex12-agonists for analgesiaxe2x80x9d, Emerging Drugs 1996, Chapter Eighteen, 377-399, Ashley Publications Ltd.) the lipid solubility of clonidine results in significant systemic absorption when administered epidurally. This results in significant systemic side-effects, such as, sedation and hypotension. It is suggested that agents with lower lipid solubility may be advantageous. Also, Eisenach J. C. in Exp. Opin. Invest. Drugs 3(10), 1994, 1005-1010, states that injectable xcex12-agonist drug development would logically focus on compounds of low lipophilicity. Increasing lipophilicity is associated with more rapid and extensive absorption into the vasculature and redistribution in the body, which for xcex12-agonists could lead to a greater likelihood or intensity of sedative and haemodynamic side-effects.
Further, Staats P. S. and Mitchell V. D. (Progr. Anesthesiol. 11(19), 1997, 367-382) state that, although clonidine has been demonstrated to be a powerful analgesic agent, the clinical use of intrathecal clonidine has been limited by side-effects, primarily hypotension and bradycardia.
Applicants have discovered that 3-(1H-imidazol-4-ylmethyl)-indan-5-ol, its enantiomer or a pharmaceutically acceptable ester or salt thereof is an ideal agent to be administered to a mammal intraspinally for obtaining analgesia. Accordingly, an object of the invention is to provide a method for obtaining analgesia by administering 3-(1H-imidazol-4-ylmethyl)-indan-5-ol, its enantiomer or a pharmaceutically acceptable ester or salt thereof to a mammal intraspinally in an amount sufficient to give the desired therapeutic effect. Applicants surprisingly discovered that 3-(1H-imidazol-4-ylmethyl)-indan-5-ol, its enantiomer or a pharmaceutically acceptable ester or salt thereof can be administered intraspinally to a mammal obtaining analgesia without side-effects, such as sedation. This is surprising because 3-(1H-imidazol-4-ylmethyl)-indan-5-ol has a considerable higher lipophilicity when compared to clonidine at physiological pH. Because of the higher lipophilicity it would have been expected that 3-(1H-imidazol-4-ylmethyl)-indan-5-ol would cause also the systemic adverse effects when administered intraspinally as clonidine does.
It should be noted that the method for obtaining analgesia in a mammal encompasses all of the potential conditions that require the treatment of pain, e.g., intraoperative pain; postoperative pain; obstetric pain; chronic pain, such as cancer-related pain and neuropathic pain; and spastic paraplegia. Further, it should be noted that intraspinal administration is intented to include epidural, intrathecal (i.e., within the spinal subarachnoid or subdural space), and intrarrhachidian administration.
An object of the invention is also to provide a method for treating a mammal by administering 3-(1H-imidazol-4-ylmethyl)-indan-5-ol, its enantiomer or a pharnmaceutically acceptable ester or salt thereof intraspinally for a time sufficient to give the therapeutic effect.
An aspect of the invention is also to provide a method of using 3-(1H-imidazol-4--ylmethyl)-indan-5-ol, its enantiomer or a pharmaceutically acceptable ester or salt thereof intraspinally as an adjunct to anaesthesia.
A further aspect of the invention relates to a use of 3-(1H-imidazol-4-ylmethyl)-indan-5-ol, its enantiomer or a pharmaceutically acceptable ester or salt thereof in the manufacture of a medicament for intraspinal administration.
In a further aspect, the invention relates to a use of 3-(1H-imidazol-4-ylmethyl)-indan-5-ol, its enantiomer or a pharmaceutically acceptable ester or salt thereof in an intraspinal administration to a mammal to obtain analgesia.
Additional objects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. The objects and advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.